Biochemical basis of the prevention of 6-thiopurine toxicity by the nucleobases, hypoxanthine and adenine.
Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10 microM, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50 microM hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.
Hashimoto
H
H
Department of Pediatrics, Kyoto University, Japan.
Kubota
M
M
Shimizu
T
T
Takimoto
T
T
Kitoh
T
T
Akiyama
Y
Y
Mikawa
H
H
D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D000225:Adenine / Q000494:pharmacology*; D000228:Adenine Phosphoribosyltransferase / Q000172:deficiency; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D006801:Humans; D019271:Hypoxanthine; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency; D007042:Hypoxanthines / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000096:biosynthesis; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015122:Mercaptopurine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D013866:Thioguanine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D013873:Thionucleotides / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D000970:Antineoplastic Agents; D007042:Hypoxanthines; D013873:Thionucleotides; D007291:Inosine Monophosphate; D019271:Hypoxanthine; D015075:2-Aminopurine; C007300:2,6-diaminopurine; C003449:thioinosinic acid; D015122:Mercaptopurine; D000228:Adenine Phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D000225:Adenine